Synthesis of thiazole-4-carboxamide-adenine difluoromethylenediphosphonates substituted with fluorine at C-2′ of the adenosine Journal Article
| Authors: | Zatorski, A.; Lipka, P.; Mollova, N.; Schram, K. H.; Goldstein, B. M.; Watanabe, K. A.; Pankiewicz, K. W. |
| Article Title: | Synthesis of thiazole-4-carboxamide-adenine difluoromethylenediphosphonates substituted with fluorine at C-2′ of the adenosine |
| Abstract: | Synthesis of an analogue 3 of thiazole-4-carboxamide adenine-dinucleotide (TAD) in which the α-oxygen atom of the pyrophosphate bridge is replaced by a difluoromethylene group has been achieved. Likewise, 2′-deoxy-2′-fluoroadenosine containing analogues of TAD (4) and its difluoromethylenediphosphonate congener (5 have been synthesized. Adenosine 5′-difluoromethylenediphosphonate (8) was prepared from 5′-O-tosyladenosine (6) and tris-tetra-n-butylammonium)difluoromethylene-diphosphonate (7) by a modified procedure of Poulter's.2 Compound 8 was converted into the 2′-3′-cyclic carbonate 9 by treatment with triethyl orthoformate. Treatment of 9 with 2′-3′-O-isopro-pylidenetiazofurin (10) in pyridine in the presence of DCC gave a mixture of dinucleotide 11 and the isopropylidene-protected diadenosine tetraphosphonate 12. After deprotection of 11, the desired β-difluoromethylene TAD (3_ was separated by HPLC as the minor product. The diadenosine tetraphosphonate 12, an analogue of Ap4A, was obtained as the major component. Alternatively, 2′-3′-O-isopropylidenetiazofurin (10) was tosylated, and the product 13 was further converted into the corresponding difluoromethylenediphosphonate 14 by coupling with 7. DCC-catalyzed coupling of 14 with 2′-deoxy-2′-fluoroadenosine (15) followed by deisopropylidenation afforded the anlogue 5. Again the corresponding tetraphosphonate analogue of tiazofurin 17 was the predominant product. Dinucleotide 4 was obtained by coupling of the carbonyldiimidazole-activated tiazofurin 5′-monophosphate with 2′-deoxy-2′-fluoroadenosine 5′-monophosphate. 2′-Deoxy-2′-fluoroadenosine (′15) was prepared efficiently from the known N6-benzoyl-3′-O-tetrahydropyranyladenosine (18), which was converted into 3′-O-tetrahydropyranyl-2′-O-triflyl-5′-O-trityladenosi ne (20) by tritylation and triflation. Treatment of 20 with sodium acetate in hexamethylphosphoric triamide, followed by deaceltylation afforded 9-(3-O-tetrahydropyranyl-5-O-trityl-β-d-arabinofuranosyl)-N6-benzoyladenine (22), which was then treated with DAST. After deprotection of the product, 15 was obtained in good yield. © 1993. |
| Keywords: | unclassified drug; mass spectrometry; drug synthesis; adenosine; magnetic resonance spectroscopy; molecular structure; high performance liquid chromatography; chemical reactions; thiazoles; carbohydrates; indicators and reagents; fluorine; adenine nucleotides; adenosine derivative; article; support, u.s. gov't, p.h.s.; spectrometry, mass, fast atom bombardment; congener; difluoromethylene group; pyrophosphate bridge; organofluorine derivative; p1 (tiazofurin 5' yl) p2 (2' deoxy 2' fluoroadenosin 5' yl) difluoromethylenediphosphonate; p1 (tiazofurin 5' yl) p2 (adenosin 5' yl)difluoromethylenediphosphonate; tiazofurin (5'-5'') 2'' deoxy 2'' fluoroadenosine pyrophosphate |
| Journal Title: | Carbohydrate Research |
| Volume: | 249 |
| Issue: | 1 |
| ISSN: | 0008-6215 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 1993-10-18 |
| Start Page: | 95 |
| End Page: | 108 |
| Language: | English |
| DOI: | 10.1016/0008-6215(93)84063-c |
| PUBMED: | 8252557 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Source: Scopus |
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43Pankiewicz
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